1. Field of the Invention
The present invention relates to polymers substituted by groups conferring anticoagulant properties on them, to the process for their preparation, to articles constituted by and/or comprising said substituted polymers, the processes for their manufacture and to the uses of said articles in surgery and in medicine, and pharmaceutical compositions containing said substituted polymers.
2. Description of the Prior Art
Heparin, the natural anticoagulant agent of the blood, constitutes a medicament of choice in thromboembolic disorders. consequently, in order to overcome the drawbacks of heparin, for a certain number of years already, attempts have been made to provide a substitute for this valuable material by various synthetic or semi-synthetic products.
In this role there have been recognized: -chondroitin sulfate, (which is also a heterogeneous polyholoside), chitosan (a scission product of chitin) prepared by the complete N-deacetylation of chitin (HORTON and JUST "carbohydrate Research" 29 (1973) 173-179), sulfated chitosan (WOLFROM and SHENHAN, JACS (1959) 81, 1764-1766), heparan sulfate (JORPES and GARDELL "J. Biol. Chem." 176-267 (1948)) and other polysaccharides formed by the polymerisation of a disaccharide unit constituted by an osamine (principally D-glucosamine) bearing a certain number of sulfate and/or sulfonate groups and by a uronic acid (generally D-glucuronic acid and L-iduronic acid). Apart from the fact that the "heparin-like" action of these various products is less pronounced than that of heparin, their natural origin is the cause (as is the case for heparin) of their variability and their heterogeneity from one preparation to the next.
Another series of heparinoids is constituted by products derived from amylose (which, like heparin has (1 4) bonds, which have been studied, among others, by WOLFROM and WANG (Carbohydrate Research 18 (1971) 23-27) relating to aminated and sulfated amylose and by HORTON and JUST (Carbohydrate Research 30 (1973) 349-357) relating to conversion of amylose into (1.fwdarw.4) 2-amino-2-deoxy-.alpha.D-glucopyranuronane. The products so obtained have a weak or practically zero heparinic activity (aminated and sulfated amylose).
Certain other polysaccharides have been indicated for their more or less anticoagulant properties: dextran sulfate (V. POTUZNIK J. Hyg. Epid. Microbiol. Immunol. 16, 293 (1972)); sulfuric polyester of pentosan (a product sold under the name "HEMOCLAR" by CLIN-MIDY Laboratories); or derivatives of alginic acid (L. LARM and collab. Carbohydr. Res. 73, 332 (1979)). Unfortunately, none of these products can be validly compared with heparin.
Sulfonated derivatives of polypeptides, namely copolymers of lysin and of tryptophane, have also been proposed (French Pat. No. 2, 280, 387). If these products in fact cause a very distinct prolongation of the coagulation time and have an action of the same type as that of heparin, they cannot be used on a large scale, since the side reactions that they cause in the human organism are extremely troublesome.
In 1975, Harry P. GREGOR (Polym. Sci. Technol. U.S.A. (1975) 7, 51-56) recognized the use, as "heparin-like" materials, of sulfonated polymers and copolymers (in particular polystyrenesulfonic and polyethylenesulfonic acids). T. BEUGELING and Collab. (J. BIOMED. MATER. RES. (1974) Vol. 8, 375-379 and BIOCOMPAT. IMPLANT. MATER, 187192 (1976)) recognized the use of polymers synthesized from polyisoprenes, of which the unit is represented as follows: ##STR1## which are derivatives containing aminosulfonate and carboxylate groups.
These Authors have obtained essentially soluble derivatives whose anticoagulant activity only represents however 12 to 15% of that of heparin taken as a reference.
Other interesting attempts have been carried out by grafting the heparin molecule itself on to the surface of polymers (for example by means of a coupling agent constituted by tridodecylmethylammonium chloride: LEININGER and Collab. in Trans. Amer. Soc. Artif. Int. Organs 18 10 (1972), etc . . . ) or by a covalent bond: (HOFFMAN and Collab. in Trans. Amer. Soc. Artif. Int. Organs. 18 10 (1972), ect . . . ). Unfortunately, apart from the fact that the fixing of only a relatively small amount of heparin has been acheived, these "heparinized" polymers are not stable: the amount fixed has a tendency to become inactivated with time.
In general, the advantage which would exist in having available a product with anticoagulant action which is not only stable, reproducible and homogeneous from one batch to the next, but also insoluble if desired, is the stimulus of numerous research studies for new anticoagulants.
Thus very active products have been obtained by chemical or radiochemical grafting or vinyl monomers on heparin (compare the work of C. BAQUEY and Collab. in Ann. Phys. Biol. Med. 9(2) 131-138 (1975) and of D. LABARRE, These de Doctorat d'Etat Paris (1977)). The insoluble polymers thus obtained are unusable in practice, since in addition to the inactivation that they undergo with time, the grafted heparin migrates to the inside of the molecule in the couse of the application of these products, and becomes completely masked.
On examining the anticoagulant properties of the various compounds enumerated above, Applicants have formulated a hypothesis according to which the anticoagulant properties of heparin are not bound up with its secondary or tertiary structure, but more precisely with the nature of the various groups borne by the polysaccharide chain and with the combination of effects of these groups, which would have a cooperative result multiplying the activity of each of them relative to the thrombin and antithrombin III.
It is considered that heparin, generally represented by the formula II below: ##STR2## possesses also non O-sulfated or 2-O-sulfated units of the uronic residue ##STR3##
In addition, ion exchange resins useful for the liquid chromatography of recemic mixtures have been prepared, which resins are essentially constituted by polystyrenes on which the following amino acids have been fixed: alanine, valine, norvaline, phenylalanine, leucine, isoleucine, tyrosine, serine, threonine, aspartic acid, proline, hydroxyproline and glutamic acid (compare in particular the studies carried out by VESA and Collab., Zh. Obsch. Khim. SSSR 42 (12) 2780 (1972) and Tr. Akad. Nauk. Lit. SSR. Ser. B. 2-69, 93 (1972) and by PETIT and JOZEFONVICZ (Jour, Of Applied Polymer Sci. Vol. 21 2589-2596 (1977)).
Starting from their hypothesis relative to the importance of the simultaneous presence of groups which figure in the above formulae II and III, on a macromolecular support, Applicants have been able to establish that such ion exchange resins have applications as agents endowed with anticoagulant action.
Better still, through their comprehension of this phenomenon and pressing their studies and their investigations still further, Applicants have been able to establish a more general formula suitable for all polymers crosslinked or not and including in their chain substitutable groups. They have been able to arrive in this way at both soluble and insoluble products, having anticoagulant properties.